The present invention relates to novel heterocyclic derivatives and related compounds, pharmaceutical compositions comprising such compounds, and the use of such compounds as regulators of the action of angiotensin II in mammals. The compounds of this invention are useful in the treatment and prevention of hypertension, glaucoma, renal disease, congestive heart failure, cognitive dysfunction, and other conditions in which the action of angiotensin II is implicated. This invention also relates to pharmaceutical compositions containing these compounds and to methods of inhibiting angiotensin II in mammals by administration of such compounds.
The renin-angiotensin system acts as a crucial regulatory mechanism in the control of homeostasis and fluid/electrolyte balance in mammals, including humans. Renin-angiotensin system activity has a direct influence on blood pressure and has been found to play an important role in congestive heart failure and in the development and maintenance of hypertension. Angiotensin II, an octapeptide hormone produced via the cleavage of angiotensin I by angiotensin converting enzyme, is a potent and direct arterial vasoconstrictor which increases vascular resistance and blood pressure. Angiotensin II activity has also been implicated in the development of elevated intraocular pressure, for example, as caused by glaucoma, and it is known to stimulate the release of aldosterone resulting in vascular congestion and hypertension by promoting the retention of sodium and fluids. The present invention concerns regulation of the actions of angiotensin II which are mediated by the angiotensin II receptor.
Various heterocyclic compounds have been described as angiotensin II antagonists. Certain compounds referred to in the literature consist of a heterocyclic ring connected via a spacer group (i.e., a connecting group) to an aryl or heterocyclic ring substituted with an acidic moiety. In certain cases the spacer group consists of a methylene group connected to an aryl or heterocyclic group. Examples of such heterocycles in spacer groups include: imidazoles (EP 450566-A, published Oct. 9, 1991; EP 468372-A, published Jan. 29, 1992; DE 4010797), furans (EP 253310-A, published Jan. 20, 1988), thiophenes (EP 449699, published Oct. 2, 1991; EP465323-A, published Jan. 8, 1992; DE 4032522, published Apr. 16, 1992), pyrroles and pyridines (EP 480204, published Apr. 15, 1992), indoles (EP 489,532, published Jun. 10, 1992), benzofurans (WO 92 09278, published Jun. 11, 1992) and benzothiophenes (WO 92 09600, published Jun. 11, 1992). (All documents cited herein, including the foregoing, are incorporated herein in their entireties.)